Two-Hit Pre-clinical Models for Parkinsonís Disease

Development of Progressive Pre-clinical Models of PD, 2006

Despite recent advances in Parkinson's disease genetics, the animal models based on identified genetic defects have not largely emulated the progressive nigral neuron degeneration that characterizes PD. Furthermore, at the population level, the contribution of each single genetic factor appears minimal, and it appears that some of the identified genetic factors may act as risk, rather than determining, factors for PD. It is likely therefore that 'sporadic' PD represents an oligogenic disease. There is a need for animal models that are based on such concepts. Such animal models may more closely resemble sporadic PD, and may offer the opportunity for investigation of pathophysiological mechanisms and therapies. We aim to generate pre-clinical models that incorporate multiple genetic defects found in PD patients.

In terms of PD pathophysiology, there are two emerging themes: protein toxicity and neuroprotection. Accumulation and aggregation of alpha-synuclein appears to contribute to dopamine neuron death through impairments in protein handling and detoxification. On the other hand, activation of Nurr1 increases the survival of dopaminergic neurons apparently by controlling the expression of neuroprotective gene(s), and relative lack of Nurr-1 is associated with susceptibility of dopaminergic neurons to degeneration.

For both the alpha-synuclein and Nurr1 genes, mutations have been identified in PD patients and the expression levels of both of alpha-synuclein and Nurr1 genes have been found to be important in the development of the disease. Thus, we will create mice bearing mutations found in PD patients for both genes and we expect that they will display progressive nigrostriatal dopaminergic degeneration, progressive striatal dopaminergic dysfunction and protein aggregation, emulating the basic features of PD. That these models incorporate the concepts of protein aggregation and lack of neuroprotection makes them more attractive as models that are more related to sporadic PD.

FINAL OUTCOME

The proposed mice were successfully created. These mice appear to develop an accelerated motor phenotype, when compared to their littermate controls. Characterization of the dopaminergic system and the neurobiological basis for this phenomenon is ongoing.